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Zhu X, Wang J, Zhang H, Yue H, Zhu J, Li J, Wang K, Shen K, Yang K, Leng X, Xi Q, Shi T. Downregulated KLF4, induced by m6A modification, aggravates intestinal barrier dysfunction in inflammatory bowel disease. Cell Mol Life Sci 2024; 81:470. [PMID: 39612002 DOI: 10.1007/s00018-024-05514-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 11/08/2024] [Accepted: 11/15/2024] [Indexed: 11/30/2024]
Abstract
BACKGROUND Krüppel-like factor 4 (KLF4), a transcription factor, is involved in various biological processes. However, the role of KLF4 in regulating the intestinal epithelial barrier (IEB) in inflammatory bowel disease (IBD) and its mechanism have not been extensively studied. METHODS KLF4 expression in IBD patients and colitis mice was analyzed using Gene Expression Omnibus(GEO) database, immunohistochemistry (IHC) and Western blot. The roles of KLF4 in IEB and colitis symptoms were verified in dextran sulfate sodium (DSS)-induced and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model mice using an adenovirus carrying KLF4 shRNA (shKLF4-Adv). Furthermore, the influence of KLF4 on trans-epithelium electrical resistance (TEER), paracellular permeability, apical junction complex (AJC) protein expression and apoptosis was assessed in vitro and in vivo. MeRIP and RIP assays were used to verify the effects of m6A modification on KLF4 expression. RESULTS KLF4 expression was significantly decreased in IBD patients and was negatively associated with inflammatory features. KLF4 deletion aggravated colitis symptoms and IEB injuries by reducing AJC protein expression and increasing apoptosis in mice with colitis. Furthermore, KLF4 transcriptionally regulated the expression of AJC proteins and inhibited apoptosis by reducing cellular ROS levels and proinflammatory cytokine expression. Moreover, we observed that METTL3/ALKBH5/YTHDF2-mediated m6A modification led to a decrease in KLF4 expression in Caco-2 cells. In addition, APTO-253, an inducer of KLF4, exhibited a synergistic effect with mesalazine on IEB function. CONCLUSIONS Our study demonstrated that KLF4 is a crucial regulator of IEB, suggesting that targeting KLF4 may be a promising therapeutic alternative for IBD.
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Affiliation(s)
- Xingchao Zhu
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China
| | - Jiayu Wang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China
| | - Huan Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China
| | - Hongqin Yue
- Department of Gastroenterology, The Yancheng School of Clinical Medicine of Nanjing Medical University (Yancheng Third People's Hospital), 75 Juchang Road, Yancheng, 224001, China
| | - Jinghan Zhu
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China
| | - Juntao Li
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China
| | - Kun Wang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China
| | - Kanger Shen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China
| | - Kexi Yang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China
| | - Xia Leng
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China
| | - Qinhua Xi
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China.
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215000, China.
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China.
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China.
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Zamanian MY, Golmohammadi M, Amin RS, Bustani GS, Romero-Parra RM, Zabibah RS, Oz T, Jalil AT, Soltani A, Kujawska M. Therapeutic Targeting of Krüppel-Like Factor 4 and Its Pharmacological Potential in Parkinson's Disease: a Comprehensive Review. Mol Neurobiol 2024; 61:3596-3606. [PMID: 37996730 PMCID: PMC11087351 DOI: 10.1007/s12035-023-03800-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 11/10/2023] [Indexed: 11/25/2023]
Abstract
Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, is found in different human tissues and shows diverse regulatory activities in a cell-dependent manner. In the brain, KLF4 controls various neurophysiological and neuropathological processes, and its contribution to various neurological diseases has been widely reported. Parkinson's disease (PD) is an age-related neurodegenerative disease that might have a connection with KLF4. In this review, we discussed the potential implication of KLF4 in fundamental molecular mechanisms of PD, including aberrant proteostasis, neuroinflammation, apoptosis, oxidative stress, and iron overload. The evidence collected herein sheds new light on KLF4-mediated pathways, which manipulation appears to be a promising therapeutic target for PD management. However, there is a gap in the knowledge on this topic, and extended research is required to understand the translational value of the KLF4-oriented therapeutical approach in PD.
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Affiliation(s)
- Mohammad Yasin Zamanian
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, 6718773654, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, 6718773654, Iran
| | - Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran
| | | | | | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Tuba Oz
- Department of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806, Poznan, Poland
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Afsaneh Soltani
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran.
| | - Małgorzata Kujawska
- Department of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806, Poznan, Poland.
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Akinsuyi OS, Xhumari J, Ojeda A, Roesch LFW. Gut permeability among Astronauts during Space missions. LIFE SCIENCES IN SPACE RESEARCH 2024; 41:171-180. [PMID: 38670644 DOI: 10.1016/j.lssr.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 02/02/2024] [Accepted: 03/13/2024] [Indexed: 04/28/2024]
Abstract
The space environment poses substantial challenges to human physiology, including potential disruptions in gastrointestinal health. Gut permeability has only recently become widely acknowledged for its potential to cause adverse effects on a systemic level, rendering it a critical factor to investigate in the context of spaceflight. Here, we propose that astronauts experience the onset of leaky gut during space missions supported by transcriptomic and metagenomic analysis of human and murine samples. A genetic map contributing to intestinal permeability was constructed from a systematic review of current literature. This was referenced against our re-analysis of three independent transcriptomic datasets which revealed significant changes in gene expression patterns associated with the gut barrier. Specifically, in astronauts during flight, we observed a substantial reduction in the expression genes that are crucial for intestinal barrier function, goblet cell development, gut microbiota modulation, and immune responses. Among rodent spaceflight studies, differential expression of cytokines, chemokines, and genes which regulate mucin production and post-translational modifications suggest a similar dysfunction of intestinal permeability. Metagenomic analysis of feces from two murine studies revealed a notable reduction probiotic, short chain fatty acid-producing bacteria and an increase in the Gram-negative pathogens, including Citrobacter rodentium, Enterobacter cloacea, Klebsiella aerogenes, and Proteus hauseri which promote LPS circulation, a recipe for barrier disruption and systemic inflammatory activation. These findings emphasize the critical need to understand the underlying mechanisms and develop interventions to maintain gastrointestinal health in space.
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Affiliation(s)
- Oluwamayowa S Akinsuyi
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA
| | - Jessica Xhumari
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA
| | - Amanda Ojeda
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA
| | - Luiz F W Roesch
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA.
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DuVall AS, Wesevich A, Larson RA. Developing Targeted Therapies for T Cell Acute Lymphoblastic Leukemia/Lymphoma. Curr Hematol Malig Rep 2023; 18:217-225. [PMID: 37490229 PMCID: PMC11748120 DOI: 10.1007/s11899-023-00706-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2023] [Indexed: 07/26/2023]
Abstract
PURPOSE OF REVIEW Largely, treatment advances in relapsed and/or refractory acute lymphoblastic leukemia (ALL) have been made in B cell disease leaving T cell ALL reliant upon high-intensity chemotherapy. Recent advances in the understanding of the biology of T-ALL and the improvement in immunotherapies have led to new therapeutic pathways to target and exploit. Here, we review the more promising pathways that are able to be targeted and other therapeutic possibilities for T-ALL. RECENT FINDINGS Preclinical models and early-phase clinical trials have shown promising results in some case in the treatment of T-ALL. Targeting many different pathways could lead to the next advancement in the treatment of relapsed and/or refractory disease. Recent advances in cellular therapies have also shown promise in this space. When reviewing the literature as a whole, targeting important pathways and antigens likely will lead to the next advancement in T-ALL survival since intensifying chemotherapy.
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Affiliation(s)
- Adam S DuVall
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, USA.
| | - Austin Wesevich
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, USA
| | - Richard A Larson
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, USA
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Jeon AY, Cho JY, Park J, Kim WJ, Kim YO, Kong HJ, Kim JW. Molecular cytogenetic analysis of the olive flounder embryonic cell line FGBC8 and its applicability to biotechnology. FISH & SHELLFISH IMMUNOLOGY 2023; 142:109077. [PMID: 37726081 DOI: 10.1016/j.fsi.2023.109077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 09/05/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023]
Abstract
We explored the biotechnological applicability of a previously established olive flounder (Paralichthys olivaceus) embryonic cell line (FGBC8). FGBC8 was transfected with pEGFP-c1 and pluripotency-related genes, then infected with viral hemorrhagic septicemia virus (VHSV), and the expression of immune-related genes was observed through quantitative real-time polymerase chain reaction. Transfected cells showed strong green fluorescence 48 h after transfection, and pluripotency-related genes were successfully transfected. In addition, FGBC8 cells were highly susceptible to VHSV and the expression of immune-related genes was induced during infection. Our results demonstrate that FGBC8 cells are valuable research tools for assessing host-pathogen interactions and biotechnological applications.
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Affiliation(s)
- A-Young Jeon
- Biotechnology Research Division, National Institute of Fisheries Science, Busan, 46083, Republic of Korea
| | - Ja Young Cho
- Biotechnology Research Division, National Institute of Fisheries Science, Busan, 46083, Republic of Korea
| | - Jungwook Park
- Biotechnology Research Division, National Institute of Fisheries Science, Busan, 46083, Republic of Korea
| | - Woo-Jin Kim
- Biotechnology Research Division, National Institute of Fisheries Science, Busan, 46083, Republic of Korea
| | - Young-Ok Kim
- Biotechnology Research Division, National Institute of Fisheries Science, Busan, 46083, Republic of Korea
| | - Hee Jeong Kong
- Biotechnology Research Division, National Institute of Fisheries Science, Busan, 46083, Republic of Korea
| | - Ju-Won Kim
- Biotechnology Research Division, National Institute of Fisheries Science, Busan, 46083, Republic of Korea.
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Fang YX, Liu YQ, Hu YM, Yang YY, Zhang DJ, Jiang CH, Wang JH, Zhang J. Shaoyao decoction restores the mucus layer in mice with DSS-induced colitis by regulating Notch signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 308:116258. [PMID: 36806347 DOI: 10.1016/j.jep.2023.116258] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/05/2023] [Accepted: 02/07/2023] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Restoring the mucus layer is a potential strategy for treating ulcerative colitis (UC). Previous studies reported that a Chinese medicine formula Shaoyao Decoction (SYD) effectively improved UC. However, the role and mechanism of SYD in restoring the mucus layer are still vague. AIM OF THE STUDY This study aimed to research the therapeutical effects and unravel the involved mechanism of SYD on DSS-evoked UC. MATERIALS AND METHODS First, the constituents of SYD were detected by UPLC-QTOF-MS/MS. Then, the DSS-induced UC model was introduced to investigate the pharmacologic action and molecular mechanism of SYD on UC. Pharmacodynamic indicators were assessed including body weight, colon length, ulcerations, disease activity index (DAI), inflammatory cytokines and histological parameters. To investigate the integrality and functions of the mucous layer, AB-PAS stain and UEA-1 stain were used to evaluate the completeness of mucous layer, as well as the maturation of goblet cells (GCs). The bacterial invasion was detected by fluorescence in situ hybridization. As to mechanism exploration, the expressions of Notch/Hes1 pathway were investigated by using agonists in lipopolysaccharides (LPS) -stimulated LS174T cell. RESULTS After modeling in mice, SYD remarkedly ameliorated the symptoms of mouse colitis, the expression of pro-inflammatory factors declined, and increased IL-10 expression was observed in SYD-treated mice. Besides, SYD repaired the structure of the mucus layer and prevented bacterial invasion. Mechanism investigation discovered that SYD promoted GCs differentiation by inhibiting the Notch pathway, which was consistent with the results in LPS-challenged LS174 cell. CONCLUSIONS These findings demonstrated that SYD could restore the mucus layer to prevent UC via suppressing the Notch signaling pathway, which provided evidences for the UC treatment of SYD in the clinic.
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Affiliation(s)
- Yu-Xi Fang
- Department of Gastroenterology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, PR China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China
| | - You-Qian Liu
- Department of Gastroenterology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, PR China
| | - Yi-Min Hu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China
| | - Yuan-Yuan Yang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China
| | - Dong-Jian Zhang
- Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, PR China
| | - Cui-Hua Jiang
- Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, PR China
| | - Jian-Hua Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China.
| | - Jian Zhang
- Department of Gastroenterology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, PR China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China.
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Liu Y, Yu Z, Zhu L, Ma S, Luo Y, Liang H, Liu Q, Chen J, Guli S, Chen X. Orchestration of MUC2 - The key regulatory target of gut barrier and homeostasis: A review. Int J Biol Macromol 2023; 236:123862. [PMID: 36870625 DOI: 10.1016/j.ijbiomac.2023.123862] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023]
Abstract
The gut mucosa of human is covered by mucus, functioning as a crucial defense line for the intestine against external stimuli and pathogens. Mucin2 (MUC2) is a subtype of secretory mucins generated by goblet cells and is the major macromolecular component of mucus. Currently, there is an increasing interest on the investigations of MUC2, noting that its function is far beyond a maintainer of the mucus barrier. Moreover, numerous gut diseases are associated with dysregulated MUC2 production. Appropriate production level of MUC2 and mucus contributes to gut barrier function and homeostasis. The production of MUC2 is regulated by a series of physiological processes, which are orchestrated by various bioactive molecules, signaling pathways and gut microbiota, etc., forming a complex regulatory network. Incorporating the latest findings, this review provided a comprehensive summary of MUC2, including its structure, significance and secretory process. Furthermore, we also summarized the molecular mechanisms of the regulation of MUC2 production aiming to provide developmental directions for future researches on MUC2, which can act as a potential prognostic indicator and targeted therapeutic manipulation for diseases. Collectively, we elucidated the micro-level mechanisms underlying MUC2-related phenotypes, hoping to offer some constructive guidance for intestinal and overall health of mankind.
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Affiliation(s)
- Yaxin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Zihan Yu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Lanping Zhu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Shuang Ma
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Yang Luo
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Huixi Liang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Qinlingfei Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Jihua Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Sitan Guli
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China.
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The Involvement of Krüppel-like Factors in Cardiovascular Diseases. Life (Basel) 2023; 13:life13020420. [PMID: 36836777 PMCID: PMC9962890 DOI: 10.3390/life13020420] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/16/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
Krüppel-like factors (KLFs) are a set of DNA-binding proteins belonging to a family of zinc-finger transcription factors, which have been associated with many biological processes related to the activation or repression of genes, inducing cell growth, differentiation, and death, and the development and maintenance of tissues. In response to metabolic alterations caused by disease and stress, the heart will undergo cardiac remodeling, leading to cardiovascular diseases (CVDs). KLFs are among the transcriptional factors that take control of many physiological and, in this case, pathophysiological processes of CVD. KLFs seem to be associated with congenital heart disease-linked syndromes, malformations because of autosomal diseases, mutations that relate to protein instability, and/or loss of functions such as atheroprotective activities. Ischemic damage also relates to KLF dysregulation because of the differentiation of cardiac myofibroblasts or a modified fatty acid oxidation related to the formation of a dilated cardiomyopathy, myocardial infarctions, left ventricular hypertrophy, and diabetic cardiomyopathies. In this review, we describe the importance of KLFs in cardiovascular diseases such as atherosclerosis, myocardial infarction, left ventricle hypertrophy, stroke, diabetic cardiomyopathy, and congenital heart diseases. We further discuss microRNAs that have been involved in certain regulatory loops of KLFs as they may act as critical in CVDs.
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Zhang Y, Yao C, Ju Z, Jiao D, Hu D, Qi L, Liu S, Wu X, Zhao C. Krüppel-like factors in tumors: Key regulators and therapeutic avenues. Front Oncol 2023; 13:1080720. [PMID: 36761967 PMCID: PMC9905823 DOI: 10.3389/fonc.2023.1080720] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 01/09/2023] [Indexed: 01/26/2023] Open
Abstract
Krüppel-like factors (KLFs) are a group of DNA-binding transcriptional regulators with multiple essential functions in various cellular processes, including proliferation, migration, inflammation, and angiogenesis. The aberrant expression of KLFs is often found in tumor tissues and is essential for tumor development. At the molecular level, KLFs regulate multiple signaling pathways and mediate crosstalk among them. Some KLFs may also be molecular switches for specific biological signals, driving their transition from tumor suppressors to promoters. At the histological level, the abnormal expression of KLFs is closely associated with tumor cell stemness, proliferation, apoptosis, and alterations in the tumor microenvironment. Notably, the role of each KLF in tumors varies according to tumor type and different stages of tumor development rather than being invariant. In this review, we focus on the advances in the molecular biology of KLFs, particularly the regulations of several classical signaling pathways by these factors, and the critical role of KLFs in tumor development. We also highlight their strong potential as molecular targets in tumor therapy and suggest potential directions for clinical translational research.
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Affiliation(s)
- Yuchen Zhang
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chongjie Yao
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China,Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ziyong Ju
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Danli Jiao
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dan Hu
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Qi
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shimin Liu
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China,Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China
| | - Xueqing Wu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Chen Zhao, ; Xueqing Wu,
| | - Chen Zhao
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Chen Zhao, ; Xueqing Wu,
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Luo DD, Zhao F. KLF4 suppresses the proliferation and metastasis of NSCLC cells via inhibition of MSI2 and regulation of the JAK/STAT3 signaling pathway. Transl Oncol 2022; 22:101396. [PMID: 35580385 PMCID: PMC9117691 DOI: 10.1016/j.tranon.2022.101396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 03/08/2022] [Accepted: 03/10/2022] [Indexed: 11/18/2022] Open
Abstract
KLF4 is downregulated, while MSI2 is upregulated in NSCLC tissues. Overexpression of KLF4 suppresses NSCLC cell migration and invasion. Knockdown of MSI2 suppresses the migration and invasion of NSCLC cells. KLF4 inhibits the transcription of MSI2 in NSCLC cells. KLF4 suppressed the invasion and migration of NSCLC cells via inhibition of JAK2/STAT3 signalling pathway. Background Non-small cell lung cancer (NSCLC) remains an aggresive tumor with poor survival rates. Krüppel-like factor 4 (KLF4) is known to be involved in progression of NSCLC; however, the detailed mechanism by which KLF4 regulates the progression of NSCLC remains unclear. Methods In order to investigate the function of KLF4 in NSCLC, cell proliferation was measured by MTT and colony formation assays. The migration and invasion of NSCLC cells were detected via wound healing and Transwell assays, respectively. Then, the interaction between KLF4 and MSI2 was confirmed using a dual-luciferase reporter assay, and the mechanism by which KLF4 regulates the tumorigenesis of NSCLC was assessed by RT-qPCR and Western blotting. Results The results showed that KLF4 was downregulated, while MSI2 was upregulated in NSCLC. Additionally, KLF4 could inhibit transcription of MSI2, and overexpression of KLF4 or knockdown of MSI2 could inhibit the proliferation, migration and invasion of NSCLC cells. Moreover, KLF4 could inhibit JAK2/STAT3 signalling pathway. Conclusions In conclusion, KLF4 significantly inhibited the proliferation, invasion and migration of NSCLC cells via inactivation of MSI2/JAK2/STAT3 signalling pathway. Thereby, our finding might shed new lights on exploring the new strategies against NSCLC.
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Lu F, Li Y, Wang X, Hu X, Liao X, Zhang Y. Early-life polyphenol intake promotes Akkermansia growth and increase of host goblet cells in association with the potential synergistic effect of Lactobacillus. Food Res Int 2021; 149:110648. [PMID: 34600650 DOI: 10.1016/j.foodres.2021.110648] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/03/2021] [Accepted: 08/18/2021] [Indexed: 12/17/2022]
Abstract
Mounting evidence suggests a critical role of gut microbiota in human colon health. Early life is a key developmental growth period, especially for building up gut microbiota and strengthening the colonic barrier. The connection between host colon and gut microbiota especially during early life is an area of increasing interest to researchers, also polyphenols improve host health through modulating this complex relationship. Postweaning (three-week-old) and adult (six-week-old) mice kept under specific pathogen-free conditions were used to investigate how early-life grape polyphenols supplementation influence the association between host colon and gut microbiota. Before grape polyphenols supplementation, postweaning mice had a higher original absolute abundance of Lactobacillus compared to adult mice. A 2-week grape polyphenols supplementation significantly boosted the abundance of Akkermansia and Lactobacillus and increased Lactobacillus-secreted lactate in postweaning mice. Early-life grape polyphenols supplementation also promoted the bloom of goblet cells and mucin 2, which benefitted both Akkermansia growth and colonic barrier. Moreover, the grape polyphenols-modulated bone morphogenetic protein (BMP), Notch and Wnt3 pathways triggered the bloom of goblet cells in GPs-administrated postweaning mice, and the increase in lactate could modulate those pathways. Meanwhile, adult mice were not affected by grape polyphenols supplementation. These results suggested that early-life polyphenol supplementation promoted Akkermansia growth and colonic barrier, which was in association with the sufficient abundance of Lactobacillus during early life. This study also indicated that Lactobacillus interact with Akkermansia through changing the physiology of host colonic goblet cells.
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Affiliation(s)
- Feng Lu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; National Engineering Research Center for Fruits and Vegetables Processing, Ministry of Science and Technology, Beijing 100083, China; Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture and Rural Affairs, Beijing 100083, China
| | - Yuanyuan Li
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; National Engineering Research Center for Fruits and Vegetables Processing, Ministry of Science and Technology, Beijing 100083, China; Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture and Rural Affairs, Beijing 100083, China
| | - Xiao Wang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; National Engineering Research Center for Fruits and Vegetables Processing, Ministry of Science and Technology, Beijing 100083, China; Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture and Rural Affairs, Beijing 100083, China
| | - Xiaosong Hu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; National Engineering Research Center for Fruits and Vegetables Processing, Ministry of Science and Technology, Beijing 100083, China; Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture and Rural Affairs, Beijing 100083, China
| | - Xiaojun Liao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; National Engineering Research Center for Fruits and Vegetables Processing, Ministry of Science and Technology, Beijing 100083, China; Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture and Rural Affairs, Beijing 100083, China
| | - Yan Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; National Engineering Research Center for Fruits and Vegetables Processing, Ministry of Science and Technology, Beijing 100083, China; Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture and Rural Affairs, Beijing 100083, China.
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12
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Yang S, Yu M. Role of Goblet Cells in Intestinal Barrier and Mucosal Immunity. J Inflamm Res 2021; 14:3171-3183. [PMID: 34285541 PMCID: PMC8286120 DOI: 10.2147/jir.s318327] [Citation(s) in RCA: 162] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/29/2021] [Indexed: 12/17/2022] Open
Abstract
Goblet cells and the mucus they secrete serve as an important barrier, preventing pathogens from invading the mucosa to cause intestinal inflammation. The perspective regarding goblet cells and mucus has changed, with current evidence suggesting that they are not passive but play a positive role in maintaining intestinal tract immunity and mucosal homeostasis. Goblet cells could obtain luminal antigens, presenting them to the underlying antigen-presenting cells (APCs) that induces adaptive immune responses. Various immunomodulatory factors can promote the differentiation and maturation of goblet cells, and the secretion of mucin. The abnormal proliferation and differentiation of goblet cells, as well as the deficiency synthesis and secretion of mucins, result in intestinal mucosal barrier dysfunction. This review provides an extensive outline of the signaling pathways that regulate goblet cell proliferation and differentiation and control mucins synthesis and secretion to elucidate how altering these pathways affects goblet functionality. Furthermore, the interaction between mucins and goblet cells in intestinal mucosal immunology is described. Therefore, the contribution of goblet cells and mucus in promoting gut defense and homeostasis is illustrated, while clarifying the regulatory mechanisms involved may allow the development of new therapeutic strategies for intestinal disorders.
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Affiliation(s)
- Songwei Yang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, Chongqing, 400030, People's Republic of China
| | - Min Yu
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China
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13
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Pocock R, Farah N, Richardson SE, Mansour MR. Current and emerging therapeutic approaches for T-cell acute lymphoblastic leukaemia. Br J Haematol 2021; 194:28-43. [PMID: 33942287 DOI: 10.1111/bjh.17310] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
T-cell ALL (T-ALL) is an aggressive malignancy of T-cell progenitors. Although survival outcomes in T-ALL have greatly improved over the past 50 years, relapsed and refractory cases remain extremely challenging to treat and those who cannot tolerate intensive treatment continue to have poor outcomes. Furthermore, T-ALL has proven a more challenging immunotherapeutic target than B-ALL. In this review we explore our expanding knowledge of the basic biology of T-ALL and how this is paving the way for repurposing established treatments and the development of novel therapeutic approaches.
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Affiliation(s)
- Rachael Pocock
- Department of Haematology, UCL Cancer Institute, University College London, London, UK
| | - Nadine Farah
- Department of Haematology, UCL Cancer Institute, University College London, London, UK
| | - Simon E Richardson
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
- Department of Haematology, University of Cambridge, Jeffrey Cheah Biomedical Centre, Cambridge, UK
| | - Marc R Mansour
- Department of Haematology, UCL Cancer Institute, University College London, London, UK
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14
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Zhang L, Tai Y, Tang S, Zhao C, Tong H, Gao J, Tang C. Compromised Ileal Mucus Barrier Due to Impaired Epithelial Homeostasis Caused by Notch1 Signaling in Cirrhotic Rats. Dig Dis Sci 2021; 66:131-142. [PMID: 32144600 DOI: 10.1007/s10620-020-06178-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/25/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND In liver cirrhosis, intestinal mucus barrier is rarely studied. AIMS This study aimed to investigate whether mucus barrier in ileum is altered in cirrhotic rats and its underlying mechanisms. METHODS Thioacetamide was injected to induce liver cirrhosis in rats. Serum from portal vein blood, and ileum and liver tissues were obtained for further analysis. Goblet cell-like Ls174T cells were cultured for in vitro experiments. RESULTS The ileal mucus was thin, loose, and porous with small bubbles in cirrhotic rats. mRNA expressions of Muc2 and TFF3 were also down-regulated in cirrhotic rats. Bacteria located near to crypts and LPS were increased in the serum from portal vein in cirrhotic rats. Smaller theca area and few goblet cells were found in cirrhotic rats compared with control. Increased proliferation of ileal epithelia was observed in cirrhotic rats. Notch1, Dll1, and Hes1 expressions were enhanced, and KLF4 expression was suppressed in ileum of cirrhotic rats. In Ls174T cells, EDTA and NICD plasmid induced NICD and Hes1 expression and suppressed KLF4 concomitantly, and mucus expression almost vanished in these cells. NICD plasmid induced more proliferation in Ls174T cells. Oppositely, after DBZ treatment, NICD and Hes1 were inhibited along with augmentation of KLF4 and increased mucous expression in Ls174T cells, while proliferation of the cells was suppressed. CONCLUSIONS In cirrhotic rats, mucus barrier was impaired. This might be attributed to increased proliferation and decreased differentiation of epithelia, which might be mediated by Notch1-Hes1-KLF4 signaling.
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Affiliation(s)
- Linhao Zhang
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Yang Tai
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Shihang Tang
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Chong Zhao
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Huan Tong
- Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Chengwei Tang
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China.
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15
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Molecular Mechanisms of Colon Cancer Progression and Metastasis: Recent Insights and Advancements. Int J Mol Sci 2020; 22:ijms22010130. [PMID: 33374459 PMCID: PMC7794761 DOI: 10.3390/ijms22010130] [Citation(s) in RCA: 207] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC), the third most common type of cancer, is the second leading cause of cancer-related mortality rates worldwide. Although modern research was able to shed light on the pathogenesis of CRC and provide enhanced screening strategies, the prevalence of CRC is still on the rise. Studies showed several cellular signaling pathways dysregulated in CRC, leading to the onset of malignant phenotypes. Therefore, analyzing signaling pathways involved in CRC metastasis is necessary to elucidate the underlying mechanism of CRC progression and pharmacotherapy. This review focused on target genes as well as various cellular signaling pathways including Wnt/β-catenin, p53, TGF-β/SMAD, NF-κB, Notch, VEGF, and JAKs/STAT3, which are associated with CRC progression and metastasis. Additionally, alternations in methylation patterns in relation with signaling pathways involved in regulating various cellular mechanisms such as cell cycle, transcription, apoptosis, and angiogenesis as well as invasion and metastasis were also reviewed. To date, understanding the genomic and epigenomic instability has identified candidate biomarkers that are validated for routine clinical use in CRC management. Nevertheless, better understanding of the onset and progression of CRC can aid in the development of early detection molecular markers and risk stratification methods to improve the clinical care of CRC patients.
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16
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Grondin JA, Kwon YH, Far PM, Haq S, Khan WI. Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies. Front Immunol 2020; 11:2054. [PMID: 33013869 PMCID: PMC7500085 DOI: 10.3389/fimmu.2020.02054] [Citation(s) in RCA: 252] [Impact Index Per Article: 50.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/28/2020] [Indexed: 12/24/2022] Open
Abstract
Throughout the gastrointestinal (GI) tract, a distinct mucus layer composed of highly glycosylated proteins called mucins plays an essential role in providing lubrication for the passage of food, participating in cell signaling pathways and protecting the host epithelium from commensal microorganisms and invading pathogens, as well as toxins and other environmental irritants. These mucins can be broadly classified into either secreted gel-forming mucins, those that provide the structural backbone for the mucus barrier, or transmembrane mucins, those that form the glycocalyx layer covering the underlying epithelial cells. Goblet cells dispersed among the intestinal epithelial cells are chiefly responsible for the synthesis and secretion of mucins within the gut and are heavily influenced by interactions with the immune system. Evidence from both clinical and animal studies have indicated that several GI conditions, including inflammatory bowel disease (IBD), colorectal cancer, and numerous enteric infections are accompanied by considerable changes in mucin quality and quantity. These changes include, but are not limited to, impaired goblet cell function, synthesis dysregulation, and altered post-translational modifications. The current review aims to highlight the structural and functional features as well as the production and immunological regulation of mucins and the impact these key elements have within the context of barrier function and host defense in intestinal inflammation.
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Affiliation(s)
- Jensine A Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Yun Han Kwon
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Parsa Mehraban Far
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Sabah Haq
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
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17
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Notch3 signalling and vascular remodelling in pulmonary arterial hypertension. Clin Sci (Lond) 2020; 133:2481-2498. [PMID: 31868216 PMCID: PMC6928565 DOI: 10.1042/cs20190835] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 11/27/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Notch signalling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1–4) regulating diverse cellular processes have been identified. Of these, Notch3 is expressed almost exclusively in vascular smooth muscle cells (VSMCs), where it is critically involved in vascular development and differentiation. Under pathological conditions, Notch3 regulates VSMC switching between the contractile and synthetic phenotypes. Abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because of the importance of Notch3 in VSMC (de)differentiation, Notch3 has been implicated in the pathophysiology of pulmonary vascular remodelling in PAH. Here we review the current literature on the role of Notch in VSMC function with a focus on Notch3 signalling in pulmonary artery VSMCs, and discuss potential implications in pulmonary artery remodelling in PAH.
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18
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Giuranno L, Roig EM, Wansleeben C, van den Berg A, Groot AJ, Dubois L, Vooijs M. NOTCH inhibition promotes bronchial stem cell renewal and epithelial barrier integrity after irradiation. Stem Cells Transl Med 2020; 9:799-812. [PMID: 32297712 PMCID: PMC7308641 DOI: 10.1002/sctm.19-0278] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 01/28/2020] [Accepted: 02/17/2020] [Indexed: 12/15/2022] Open
Abstract
Hyperactivity of the NOTCH pathway is associated with tumor growth and radiotherapy resistance in lung cancer, and NOTCH/γ-secretase inhibitors (GSIs) are a potential therapeutic target. The therapeutic outcome, however, is often restricted by the dose-limiting toxicity of combined treatments on the surrounding healthy tissue. The NOTCH signaling pathway is also crucial for homeostasis and repair of the normal airway epithelium. The effects of NOTCH/γ-secretase inhibition on the irradiation of normal lung epithelium are unknown and may counteract antitumor activity. Here we, therefore, investigated whether normal tissue toxicity to radiation is altered upon NOTCH pathway inhibition. We established air-liquid interface pseudostratified and polarized cultures from primary human bronchial epithelial cells and blocked NOTCH signaling alone or after irradiation with small-molecule NOTCH inhibitor/GSI. We found that the reduction in proliferation and viability of bronchial stem cells (TP63+) in response to irradiation is rescued with concomitant NOTCH inhibition. This correlated with reduced activation of the DNA damage response and accelerated repair by 24 hours and 3 days postirradiation. The increase in basal cell proliferation and viability in GSI-treated and irradiated cultures resulted in an improved epithelial barrier function. Comparable results were obtained after in vivo irradiation, where the combination of NOTCH inhibition and irradiation increased the percentage of stem cells and ciliated cells ex vivo. These encourage further use of normal patient tissue for toxicity screening of combination treatments and disclose novel interactions between NOTCH inhibition and radiotherapy and opportunities for tissue repair after radiotherapy.
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Affiliation(s)
- Lorena Giuranno
- Department of Radiotherapy, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Eloy M Roig
- Department of Radiotherapy, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Carolien Wansleeben
- Department of Radiotherapy, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Annette van den Berg
- Department of Radiotherapy, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Arjan J Groot
- Department of Radiotherapy, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Ludwig Dubois
- Department of Radiotherapy, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Marc Vooijs
- Department of Radiotherapy, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
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19
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Thabassum Akhtar Iqbal S, Tirupathi Pichiah PB, Raja S, Arunachalam S. Paeonol Reverses Adriamycin Induced Cardiac Pathological Remodeling through Notch1 Signaling Reactivation in H9c2 Cells and Adult Zebrafish Heart. Chem Res Toxicol 2020; 33:312-323. [PMID: 31307187 DOI: 10.1021/acs.chemrestox.9b00093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Adriamycin is a commonly prescribed chemotherapeutic drug for a wide range of cancers. Adriamycin causes cardiotoxicity as an adverse effect that limits its clinical application in cancer treatment. Several mechanisms have been proposed to explain the toxicity it causes in heart cells. Disruption of inherent cardiac repair mechanism is the least understood mechanism of Adriamycin-induced cardiotoxicity. Adriamycin induces pathological remodeling in cardiac cells by promoting apoptosis, hypertrophy, and fibrosis. We found that Adriamycin inhibited Notch1 in a time- and dose-dependent manner in H9c2 cells. We used Paeonol, a Notch1 activator, and analyzed the markers of apoptosis, hypertrophy, and fibrosis in H9c2 cells in vitro and in adult zebrafish heart in vivo as model systems to study Adriamycin-induced cardiotoxicity. Paeonol activated Notch1 signaling and expression of its downstream target genes effectively in the Adriamycin-treated condition in vitro and in vivo. Also we detected that Notch activation using Paeonol protected the cells from apoptosis, collagen deposition, and hypertrophy response using functional assays. We conclude that Adriamycin induced cardiotoxicity by promoting the pathological cardiac remodeling through inhibition of Notch1 signaling and that the Notch1 reactivation by Paeonol protected the cells and reversed the cardiotoxicity.
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Affiliation(s)
- Syeda Thabassum Akhtar Iqbal
- School of Bio-Sciences and Technology , Vellore Institute of Technology , Vellore , Tamilnadu PIN 632014 , India
| | | | - Sudhakaran Raja
- School of Bio-Sciences and Technology , Vellore Institute of Technology , Vellore , Tamilnadu PIN 632014 , India
| | - Sankarganesh Arunachalam
- Department of Biotechnology , Kalasalingam Academy of Research and Education , Krishnankoil , Virudhunagar, Tamilnadu PIN 626126 , India
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20
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Agbo KC, Huang JZ, Ghaleb AM, Williams JL, Shroyer KR, Bialkowska AB, Yang VW. Loss of the Krüppel-like factor 4 tumor suppressor is associated with epithelial-mesenchymal transition in colorectal cancer. ACTA ACUST UNITED AC 2019; 5. [PMID: 32566755 PMCID: PMC7304562 DOI: 10.20517/2394-4722.2019.35] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Aim: Colorectal cancer (CRC) is the third leading cancer-related cause of death due to its propensity to metastasize. Epithelial-mesenchymal transition (EMT) is a multistep process important for invasion and metastasis of CRC. Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor highly expressed in differentiated cells of the intestinal epithelium. KLF4 has been shown to play a tumor suppressor role during CRC tumorigenesis - its loss accelerates development and progression of cancer. The present study examined the relationship between KLF4 and markers of EMT in CRC. Methods: Immunofluorescence staining for KLF4 and EMT markers was performed on archived patient samples after colorectal cancer resection and on colonic tissues of mice with colitis-associated cancer. Results: We found that KLF4 expression is lost in tumor sections obtained from CRC patients and in those of mouse colon following azoxymethane and dextran sodium sulfate (AOM/DSS) treatment when compared to their respective normal appearing mucosa. Importantly, in CRC patient tumor sections, we observed a negative correlation between KLF4 levels and mesenchymal markers including TWIST, β-catenin, claudin-1, N-cadherin, and vimentin. Similarly, in tumor tissues from AOM/DSS-treated mice, KLF4 levels were negatively correlated with mesenchymal markers including SNAI2, β-catenin, and vimentin and positively correlated with the epithelial marker E-cadherin. Conclusion: These findings suggest that the loss of KLF4 expression is a potentially significant indicator of EMT in CRC.
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Affiliation(s)
- Kimberley C Agbo
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
| | - Jessie Z Huang
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
| | - Amr M Ghaleb
- Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
| | - Jennie L Williams
- Department of Family, Population and Preventive Medicine, Stony Brook, NY 11794, USA
| | - Kenneth R Shroyer
- Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
| | - Agnieszka B Bialkowska
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
| | - Vincent W Yang
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.,Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
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21
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Bagadia P, Huang X, Liu TT, Murphy KM. Shared Transcriptional Control of Innate Lymphoid Cell and Dendritic Cell Development. Annu Rev Cell Dev Biol 2019; 35:381-406. [PMID: 31283378 PMCID: PMC6886469 DOI: 10.1146/annurev-cellbio-100818-125403] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Innate immunity and adaptive immunity consist of highly specialized immune lineages that depend on transcription factors for both function and development. In this review, we dissect the similarities between two innate lineages, innate lymphoid cells (ILCs) and dendritic cells (DCs), and an adaptive immune lineage, T cells. ILCs, DCs, and T cells make up four functional immune modules and interact in concert to produce a specified immune response. These three immune lineages also share transcriptional networks governing the development of each lineage, and we discuss the similarities between ILCs and DCs in this review.
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Affiliation(s)
- Prachi Bagadia
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
| | - Xiao Huang
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
| | - Tian-Tian Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
| | - Kenneth M Murphy
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
- Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA
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22
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Yi J, Bergstrom K, Fu J, Shan X, McDaniel JM, McGee S, Qu D, Houchen CW, Liu X, Xia L. Dclk1 in tuft cells promotes inflammation-driven epithelial restitution and mitigates chronic colitis. Cell Death Differ 2019; 26:1656-1669. [PMID: 30478383 PMCID: PMC6748088 DOI: 10.1038/s41418-018-0237-x] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 09/28/2018] [Accepted: 10/22/2018] [Indexed: 12/16/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by defective intestinal barrier integrity toward the microbiota and epithelial damage. Double cortin-like kinase 1 (Dclk1), a marker of intestinal tuft cells, can regulate tissue regenerative responses, but its role in epithelial repair during bacterial-dependent chronic colitis is unclear. We addressed this question using our recently developed mouse model of spontaneous microbiota-dependent colitis induced by mucin-type O-glycan deficiency (DKO), which recapitulates most features of human UC. We generated DKO mice lacking intestinal epithelial Dclk1 (DKO;Dclk1ΔIEC) and analyzed colitis onset and severity using clinical and histologic indices, immune responses by qPCR and immunostaining, and epithelial responses using proliferation markers and organoid culture. We found 3-4-week-old DKO;Dclk1ΔIEC mice developed worsened spontaneous colitis characterized by reduced body weight, loose stool, severe colon thickening, epithelial lesions, and inflammatory cell infiltrates compared with DKO mice. The primary defect was an impaired epithelial proliferative response during inflammation. Dclk1 deficiency also reduced inflammation-induced proliferation and growth of colon organoids ex vivo. Mechanistically, Dclk1 expression was important for inflammation-induced Cox2 expression and prostaglandin E2 (PGE2) production in vivo, and PGE2 rescued proliferative defects in Dclk1-deficient colonic organoids. Although tuft cells were expanded in both DKO and DKO;Dclk1ΔIEC relative to WT mice, loss of Dclk1 was associated with reduced tuft cell activation (i.e., proliferation) during inflammation. Similar results were found in DKO vs. DKO;Dclk1ΔIEC mice at 3-6 months of age. Our results support that tuft cells, via Dclk1, are important responders to bacterial-induced colitis by enhancing epithelial repair responses, which in turn limits bacterial infiltration into the mucosa.
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Affiliation(s)
- Jun Yi
- Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Kirk Bergstrom
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Jianxin Fu
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Xindi Shan
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - J Michael McDaniel
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Samuel McGee
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Dongfeng Qu
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Courtney W Houchen
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China.
| | - Lijun Xia
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
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23
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Puerarin prevents high-fat diet-induced obesity by enriching Akkermansia muciniphila in the gut microbiota of mice. PLoS One 2019; 14:e0218490. [PMID: 31233515 PMCID: PMC6590871 DOI: 10.1371/journal.pone.0218490] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 06/02/2019] [Indexed: 12/13/2022] Open
Abstract
Growing evidence indicates that the gut microbiota plays a significant role in the pathophysiological processes of obesity and its related metabolic symptoms in the host. Puerarin, an active ingredient in the root of Pueraria lobate has been suggested to have a potent anti-obesity effect. Herein, we tested whether this effect of puerarin is associated with changes in the gut microbiota. In addition to reducing body weight, inflammation, and insulin resistance, puerarin administration significantly altered the composition of the gut microbiota. Notably, puerarin treatment greatly increased the abundance of Akkermansia muciniphila, a mucin-degrading bacterium known to be beneficial for host metabolism and significantly downregulated in high-fat diet–fed mice. Further experiments revealed that puerarin increased intestinal expression levels of Muc2 and Reg3g and protected intestinal barrier function (normal permeability) by increasing the expression of ZO-1 and occludin in vivo and in vitro. These data suggest that puerarin’s enriching effect on A. muciniphila is mediated, at least in part, by a host cellular response to protect the host from diet-induced metabolic disorders and other diseases.
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24
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Chandrasekaran B, Pal D, Kolluru V, Tyagi A, Baby B, Dahiya NR, Youssef K, Alatassi H, Ankem MK, Sharma AK, Damodaran C. The chemopreventive effect of withaferin A on spontaneous and inflammation-associated colon carcinogenesis models. Carcinogenesis 2018; 39:1537-1547. [PMID: 30124785 PMCID: PMC6314334 DOI: 10.1093/carcin/bgy109] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/06/2018] [Accepted: 08/09/2018] [Indexed: 02/05/2023] Open
Abstract
Chemopreventive effects and associated mechanisms of withaferin A (WA) against intestinal and colon carcinogenesis remain unknown. We investigated the chemopreventive effect of WA on transgenic adenomatous polyposis coli (APCMin/+) mouse and chemically induced azoxymethane/dextran sodium sulfate (AOM/DSS) models of intestinal and colon carcinogenesis. Oral WA administration (4 and 3 mg/kg) inhibited tumor initiation and progression of intestinal polyps formation in APCMin/+ mice and colon carcinogenesis in the AOM/DSS mouse model. WA-administered mice showed a significant reduction in both number [duodenum, 33% (P > 0.05); jejunum, 32% (P < 0.025); ileum, 43% ( P < 0.001); and colon 59% (P < 0.01] and size of polyps in APCMin/+ mice compared with the respective controls. Similarly, tumor multiplicity was significantly reduced (P < 0.05) in the colon of WA-administered AOM/DSS mice. Pathological analysis showed reduced adenomas and tissue inflammation in WA-administered mouse models. Molecular studies suggested that WA inhibited the expression of inflammatory (interluekin-6, tumor necrosis factor-alpha and cyclooxygenase-2), pro-survival (pAKT, Notch1 and NF-κB) markers in APCMin/+ and AOM/DSS models. The results suggest that WA is a potent agent for preventing colon carcinogenesis and further investigation is required to show clinical utility of the agent.
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Affiliation(s)
| | - Deeksha Pal
- Department of Urology, University of Louisville, Louisville, KY, USA
| | - Venkatesh Kolluru
- Department of Urology, University of Louisville, Louisville, KY, USA
| | - Ashish Tyagi
- Department of Urology, University of Louisville, Louisville, KY, USA
| | - Becca Baby
- Department of Urology, University of Louisville, Louisville, KY, USA
| | - Nisha R Dahiya
- Department of Urology, University of Louisville, Louisville, KY, USA
| | - Khafateh Youssef
- Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, USA
| | - Houda Alatassi
- Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, USA
| | - Murali K Ankem
- Department of Urology, University of Louisville, Louisville, KY, USA
| | - Arun K Sharma
- Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, USA
| | - Chendil Damodaran
- Department of Urology, University of Louisville, Louisville, KY, USA
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25
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Wang L, Shen F, Stroehlein JR, Wei D. Context-dependent functions of KLF4 in cancers: Could alternative splicing isoforms be the key? Cancer Lett 2018; 438:10-16. [PMID: 30217565 DOI: 10.1016/j.canlet.2018.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 08/10/2018] [Accepted: 09/02/2018] [Indexed: 01/15/2023]
Abstract
Krüppel-like factor 4 (KLF4) is an important transcription factor that is expressed in a variety of tissues and regulates many critical physiologic and cellular processes, including cell proliferation, differentiation, stem cell reprogramming, maintenance of genomic stability, and normal tissue homeostasis. KLF4 has both tumor suppressive and oncogenic functions in gastrointestinal and other cancers. These functions are thought to be context dependent, but how KLF4 exerts these differential functions and the molecular mechanisms behind them remain poorly understood. Recent studies have shown that the KLF4 gene undergoes alternative splicing, and the protein products of certain transcripts antagonize wild-type KLF4 function, suggesting an additional layer of regulation of KLF4 function. Therefore, detailed study of KLF4 alternative splicing may not only provide new insights into the complexity of KLF4 functions but also lead to rational targeting of KLF4 for cancer prevention and therapy.
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Affiliation(s)
- Liang Wang
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Feng Shen
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John R Stroehlein
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daoyan Wei
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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26
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Chen W, Zhuo M, Lu X, Xia X, Zhao Y, Huang Z, Xu J, Li W, Yu C. SRC-3 protects intestine from DSS-induced colitis by inhibiting inflammation and promoting goblet cell differentiation through enhancement of KLF4 expression. Int J Biol Sci 2018; 14:2051-2064. [PMID: 30585268 PMCID: PMC6299374 DOI: 10.7150/ijbs.28576] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 10/03/2018] [Indexed: 02/06/2023] Open
Abstract
Goblet cell loss, which leads to the reduction of mucin secretion, is a hallmark of ulcerative colitis (UC). We previously reported that steroid receptor coactivator 3 (SRC-3), a transcriptional coactivator, contributes to host defense against Citrobacter rodentium by recruiting neutrophils, suggesting a role of SRC-3 in intestine homeostasis. However, the biological role of SRC-3 in UC remains unclear. Here, we showed that SRC-3-/- mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis compared with wild-type mice after oral administration of 2% DSS dissolved in drinking water. After oral administration of 2% DSS, SRC-3-/- mice displayed higher mortality rate, significant body weight loss, and higher clinical symptom scores compared to wild-type mice. SRC-3-/- mice suffered a severe loss of mature colonic goblet cells, leading to more severe histopathology and more proinflammatory cytokine production. Mechanistically, SRC-3-/- mice exhibited a decreased expression of transcription factor KLF4 in the colons, which is responsible for colonic goblet cell differentiation and maturation. At the molecular level, SRC-3 cooperated with c-Fos to promote KLF4 expression at the transcriptional level. These results demonstrate that SRC-3 can ameliorate DSS-induced colitis by inhibiting inflammation and promoting colonic goblet cell differentiation and maturation through enhancing the expression of transcriptional factor KLF4, which is responsible for colonic goblet cell differentiation and maturation.
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Affiliation(s)
- Wenbo Chen
- Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China.,State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Minghui Zhuo
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xuqiang Lu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xiaochun Xia
- Xiamen Medical College, Xiamen Fujian 361023,China
| | - Yang Zhao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zhengrong Huang
- Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jianming Xu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Weihua Li
- Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Chundong Yu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
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27
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Yu M, Hao B, Zhan Y, Luo G. Krüppel-like factor 4 expression in solid tumor prognosis: A meta-analysis. Clin Chim Acta 2018; 485:50-59. [PMID: 29940144 DOI: 10.1016/j.cca.2018.06.030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 06/19/2018] [Accepted: 06/21/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Accumulating studies have demonstrated that Krüppel-like factor 4 (KLF4) can act as a tumor suppressor or oncogene in the carcinogenesis of diverse cancers. The prognostic value of KLF4 in various human solid cancers remains controversial. Thus, the present meta-analysis was conducted to evaluate the prognostic value of KLF4 in solid tumors. METHODS Eligible literature was retrieved by searching the PubMed, Embase, and Cochrane Library. Combined hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were assessed using fixed-effects and random-effects models. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. In addition, publication bias was assessed using Begg's funnel plot and Egger's regression asymmetry test. RESULTS The 22 eligible studies finally enrolled a total of 2988 patients to assess the prognostic value of KLF4 in solid tumors. Low KLF4 expression was clearly related to worse OS (HR = 1.71, 95% confidence interval [CI] = 1.30-2.24, P < 0.001) and DFS (HR = 1.74, 95% CI = 1.34-2.26, P < 0.001), indicating that low KLF4 expression could be an independent prognostic factor for poor survival in solid cancers. CONCLUSION KLF4 might be a potential marker to predict prognosis in solid cancer patients.
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Affiliation(s)
- Miaomei Yu
- Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Bo Hao
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Yuxia Zhan
- Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Guanghua Luo
- Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.
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28
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Sosa Iglesias V, Giuranno L, Dubois LJ, Theys J, Vooijs M. Drug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting? Front Oncol 2018; 8:267. [PMID: 30087852 PMCID: PMC6066509 DOI: 10.3389/fonc.2018.00267] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 06/29/2018] [Indexed: 12/14/2022] Open
Abstract
Drug resistance is a major cause for therapeutic failure in non-small cell lung cancer (NSCLC) leading to tumor recurrence and disease progression. Cell intrinsic mechanisms of resistance include changes in the expression of drug transporters, activation of pro-survival, and anti-apoptotic pathways, as well as non-intrinsic influences of the tumor microenvironment. It has become evident that tumors are composed of a heterogeneous population of cells with different genetic, epigenetic, and phenotypic characteristics that result in diverse responses to therapy, and underlies the emergence of resistant clones. This tumor heterogeneity is driven by subpopulations of tumor cells termed cancer stem cells (CSCs) that have tumor-initiating capabilities, are highly self-renewing, and retain the ability for multi-lineage differentiation. CSCs have been identified in NSCLC and have been associated with chemo- and radiotherapy resistance. Stem cell pathways are frequently deregulated in cancer and are implicated in recurrence after treatment. Here, we focus on the NOTCH signaling pathway, which has a role in stem cell maintenance in non-squamous non-small lung cancer, and we critically assess the potential for targeting the NOTCH pathway to overcome resistance to chemotherapeutic and targeted agents using both preclinical and clinical evidence.
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Affiliation(s)
- Venus Sosa Iglesias
- Department of Radiation Oncology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), Maastricht, Netherlands
| | - Lorena Giuranno
- Department of Radiation Oncology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), Maastricht, Netherlands
| | - Ludwig J Dubois
- Department of Radiation Oncology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), Maastricht, Netherlands
| | - Jan Theys
- Department of Radiation Oncology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), Maastricht, Netherlands
| | - Marc Vooijs
- Department of Radiation Oncology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), Maastricht, Netherlands
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29
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Fernandez N, Wrzosek L, Radziwill-Bienkowska JM, Ringot-Destrez B, Duviau MP, Noordine ML, Laroute V, Robert V, Cherbuy C, Daveran-Mingot ML, Cocaign-Bousquet M, Léonard R, Robbe-Masselot C, Rul F, Ogier-Denis E, Thomas M, Mercier-Bonin M. Characterization of Mucus-Related Properties of Streptococcus thermophilus: From Adhesion to Induction. Front Physiol 2018; 9:980. [PMID: 30087622 PMCID: PMC6067005 DOI: 10.3389/fphys.2018.00980] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/03/2018] [Indexed: 12/21/2022] Open
Abstract
Mucus is a major component of the intestinal barrier involved both in the protection of the host and the fitness of commensals of the gut. Streptococcus thermophilus is consumed world-wide in fermented dairy products and is also recognized as a probiotic, as its consumption is associated with improved lactose digestion. We determined the overall effect of S. thermophilus on the mucus by evaluating its ability to adhere, degrade, modify, or induce the production of mucus and/or mucins. Adhesion was analyzed in vitro using two types of mucins (from pig or human biopsies) and mucus-producing intestinal HT29-MTX cells. The induction of mucus was characterized in two different rodent models, in which S. thermophilus is the unique bacterial species in the digestive tract or transited as a sub-dominant bacterium through a complex microbiota. S. thermophilus LMD-9 and LMG18311 strains did not grow in sugars used to form mucins as the sole carbon source and displayed weak binding to mucus/mucins relative to the highly adhesive TIL448 Lactococcus lactis. The presence of S. thermophilus as the unique bacteria in the digestive tract of gnotobiotic rats led to accumulation of lactate and increased the number of Alcian-Blue positive goblet cells and the amount of the mucus-inducer KLF4 transcription factor. Lactate significantly increased KLF4 protein levels in HT29-MTX cells. Introduction of S. thermophilusvia transit as a sub-dominant bacterium (103 CFU/g feces) in a complex endogenous microbiota resulted in a slight increase in lactate levels in the digestive tract, no induction of overall mucus production, and moderate induction of sulfated mucin production. We thus show that although S. thermophilus is a poor mucus-adhesive bacterium, it can promote mucus pathway at least in part by producing lactate in the digestive tract.
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Affiliation(s)
- Neïké Fernandez
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Laura Wrzosek
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | | | - Belinda Ringot-Destrez
- Université de Lille, Lille, France.,USTL, UGSF, IFR 147, CNRS, Villeneuve-d'Ascq, France.,UMR 8576, Unité de Glycobiologie Structurale et Fonctionnelle, Villeneuve-d'Ascq, France
| | | | - Marie-Louise Noordine
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Valérie Laroute
- LISBP, CNRS, INRA, INSA, Université de Toulouse, Toulouse, France
| | - Véronique Robert
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Claire Cherbuy
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | | | | | - Renaud Léonard
- Université de Lille, Lille, France.,USTL, UGSF, IFR 147, CNRS, Villeneuve-d'Ascq, France.,UMR 8576, Unité de Glycobiologie Structurale et Fonctionnelle, Villeneuve-d'Ascq, France
| | - Catherine Robbe-Masselot
- Université de Lille, Lille, France.,USTL, UGSF, IFR 147, CNRS, Villeneuve-d'Ascq, France.,UMR 8576, Unité de Glycobiologie Structurale et Fonctionnelle, Villeneuve-d'Ascq, France
| | - Françoise Rul
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Eric Ogier-Denis
- INSERM, Research Centre of Inflammation BP 416, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,Laboratory of Excellence Labex INFLAMEX, Université Sorbonne Paris Cité, Paris, France
| | - Muriel Thomas
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Muriel Mercier-Bonin
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
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30
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Bellavia D, Palermo R, Felli MP, Screpanti I, Checquolo S. Notch signaling as a therapeutic target for acute lymphoblastic leukemia. Expert Opin Ther Targets 2018. [PMID: 29527929 DOI: 10.1080/14728222.2018.1451840] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the therapy of ALL has significantly improved, the heterogeneous genetic landscape of the disease often causes relapse, which is difficult to treat. Achieving a positive outcome for patients with relapsed or refractory ALL remains a challenging issue. The high prevalence of NOTCH-activating mutations in T-cell acute lymphoblastic leukemia (T-ALL) and the central role of NOTCH signaling in regulating cell survival and growth of ALL provide a rationale for the development of Notch signaling-targeted strategies in this disease. Therapeutic alternatives with effective anti-leukemic potential and low toxicity are needed. Areas covered: This review provides an overview of the currently available drugs directly or indirectly targeting Notch signaling in ALL. Besides considering the known Notch targeting approaches, such as γ-secretase inhibitors (GSIs) and Notch inhibiting antibodies (mAbs), currently in clinical trials, we focus on the recent insights into the molecular mechanisms underlying the Notch signaling regulation in ALL. Expert opinion: Novel drugs targeting specific steps of Notch signaling or intersecting pathways could improve the efficiency of the conventional hematological cancers therapies. Further studies are required to translate the new findings into future clinical applications.
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Affiliation(s)
- Diana Bellavia
- a Department of Molecular Medicine , Sapienza University , Rome , Italy
| | - Rocco Palermo
- b Center for Life Nano Science@Sapienza , Istituto Italiano di Tecnologia , Rome , Italy
| | - Maria Pia Felli
- c Department of Experimental Medicine , Sapienza University , Rome , Italy
| | - Isabella Screpanti
- a Department of Molecular Medicine , Sapienza University , Rome , Italy.,b Center for Life Nano Science@Sapienza , Istituto Italiano di Tecnologia , Rome , Italy.,d Institute Pasteur-Foundation Cenci Bolognetti , Sapienza University , Rome , Italy
| | - Saula Checquolo
- e Department of Medico-Surgical Sciences and Biotechnology , Sapienza University , Latina , Italy
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31
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Strobl H, Krump C, Borek I. Micro-environmental signals directing human epidermal Langerhans cell differentiation. Semin Cell Dev Biol 2018; 86:36-43. [PMID: 29448069 DOI: 10.1016/j.semcdb.2018.02.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 12/12/2017] [Accepted: 02/10/2018] [Indexed: 01/11/2023]
Abstract
Human Langerhans cells (LC) can be generated ex vivo from hematopoietic precursor cells in response to cytokines and cell-membrane associated ligands. These in vitro differentiation models provided mechanistic insights into the molecular and cellular pathways underlying the development of this unique, epithelia-associated dendritic cell subset. Notably, the human epidermal microenvironment is fully sufficient to induce LC differentiation from hematopoietic progenitors. Hence, dissecting the molecular characteristics of the human epithelial/epidermal LC niche, and testing defined ligands for their capacity to induce LC differentiation, led to a refined molecular model of LC lineage commitment. During epidermal ontogeny, spatially and temporally regulated availability of TGF-β family members cooperate with other keratinocyte-derived signals, such as E-cadherin and Notch ligands, for instructing LC differentiation. In this review, we discuss the signals known to instruct human hematopoietic progenitor cells and myelomonocytic cells to undergo LC lineage commitment. Additionally, the current methods for generation of large numbers of human LC-like cells ex vivo in defined serum-free media are discussed.
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Affiliation(s)
- Herbert Strobl
- Otto Loewi Research Center, Chair of Immunology and Pathophysiology, Medical University of Graz, Graz, Austria.
| | - Corinna Krump
- Otto Loewi Research Center, Chair of Immunology and Pathophysiology, Medical University of Graz, Graz, Austria
| | - Izabela Borek
- Otto Loewi Research Center, Chair of Immunology and Pathophysiology, Medical University of Graz, Graz, Austria
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32
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Lee SI, Kim DK, Seo EJ, Choi EJ, Kwon YW, Jang IH, Lee JC, Kim HY, Shong M, Kim JH, Kim SJ. Role of Krüppel-Like Factor 4 in the Maintenance of Chemoresistance of Anaplastic Thyroid Cancer. Thyroid 2017; 27:1424-1432. [PMID: 28920531 DOI: 10.1089/thy.2016.0414] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Anaplastic thyroid cancer (ATC) has a very poor prognosis due to its aggressive nature and resistance to conventional treatment. Radiotherapy and chemotherapy are not fully effective because of the undifferentiated phenotype and enhanced drug resistance of ATC. The objective of this study was to evaluate the involvement of Krüppel-like factor 4 (KLF4), a stemness-associated transcription factor, in the undifferentiated phenotype and drug resistance of ATC. METHODS ATC cells were compared to papillary thyroid cancer cells in drug resistance and gene expression. The effects of KLF4 knockdown in ATC cells on in vitro and in vivo drug resistance were measured. The effects of KLF4 overexpression and knockdown on ABC transporter activity were determined. RESULTS ATC cells, such as HTH83, 8505C, and SW1736, exhibited higher resistance to the anticancer drug paclitaxel and higher expression of KLF4 than TPC-1 papillary thyroid cancer cells. Knockdown of KLF4 expression in ATC cells increased the expression of the thyroid-specific differentiation genes, such as thyrotropin receptor, thyroid peroxidase, thyroglobulin, and sodium-iodide symporter. Knockdown of KLF4 expression in ATC cells decreased the resistance to doxorubicin and paclitaxel, and reduced ABC transporter expression. Luciferase reporter assay results showed that KLF4 overexpression increased ABCG2 promoter activity, which was abolished by KLF4 knockdown. A tumorigenicity assay showed that the combination of paclitaxel treatment and KLF4 knockdown significantly decreased tumor mass originated from HTH83 cells in mice. CONCLUSIONS ATC cells show high expression of KLF4, and KLF4 expression is necessary for maintaining the undifferentiated phenotype and drug resistance in vitro and in vivo. The present study identifies KLF4 as a potential therapeutic target for eliminating ATC cells.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Animals
- Antineoplastic Agents/metabolism
- Antineoplastic Agents/pharmacology
- Cell Differentiation
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Doxorubicin/metabolism
- Doxorubicin/pharmacology
- Drug Resistance, Neoplasm/genetics
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Humans
- Kruppel-Like Factor 4
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism
- Male
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Paclitaxel/metabolism
- Paclitaxel/pharmacology
- Phenotype
- Promoter Regions, Genetic
- RNA Interference
- Signal Transduction/drug effects
- Thyroid Carcinoma, Anaplastic/drug therapy
- Thyroid Carcinoma, Anaplastic/genetics
- Thyroid Carcinoma, Anaplastic/metabolism
- Thyroid Carcinoma, Anaplastic/pathology
- Thyroid Neoplasms/drug therapy
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/metabolism
- Thyroid Neoplasms/pathology
- Time Factors
- Transfection
- Tumor Burden/drug effects
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Su In Lee
- 1 Department of Physiology, School of Medicine, Pusan National University , Yangsan, Republic of Korea
| | - Dae Kyoung Kim
- 1 Department of Physiology, School of Medicine, Pusan National University , Yangsan, Republic of Korea
| | - Eun Jin Seo
- 1 Department of Physiology, School of Medicine, Pusan National University , Yangsan, Republic of Korea
| | - Eun Jung Choi
- 1 Department of Physiology, School of Medicine, Pusan National University , Yangsan, Republic of Korea
| | - Yang Woo Kwon
- 1 Department of Physiology, School of Medicine, Pusan National University , Yangsan, Republic of Korea
| | - Il Ho Jang
- 2 Department of Oral Biochemistry and Molecular Biology, School of Dentistry, Pusan National University , Yangsan, Republic of Korea
| | - Jin Choon Lee
- 3 Department of Otolaryngology, Pusan National University Yangsan Hospital , Yangsan, Republic of Korea
| | - Hyun Yul Kim
- 4 Department of Surgery, Pusan National University Yangsan Hospital , Yangsan, Republic of Korea
- 5 Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital , Yangsan, Republic of Korea
| | - Minho Shong
- 6 Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine , Daejeon, Republic of Korea
| | - Jae Ho Kim
- 1 Department of Physiology, School of Medicine, Pusan National University , Yangsan, Republic of Korea
- 5 Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital , Yangsan, Republic of Korea
| | - Seong-Jang Kim
- 7 Department of Nuclear Medicine, Pusan National University Yangsan Hospital , Yangsan, Republic of Korea
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Yang Q, Wang S, Dai E, Zhou S, Liu D, Liu H, Meng Q, Jiang B, Jiang W. Pathway enrichment analysis approach based on topological structure and updated annotation of pathway. Brief Bioinform 2017; 20:168-177. [DOI: 10.1093/bib/bbx091] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Indexed: 12/31/2022] Open
Affiliation(s)
- Qian Yang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, People’s Republic of China
| | - Shuyuan Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, People’s Republic of China
| | - Enyu Dai
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, People’s Republic of China
| | - Shunheng Zhou
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, People’s Republic of China
| | - Dianming Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, People’s Republic of China
| | - Haizhou Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, People’s Republic of China
| | - Qianqian Meng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, People’s Republic of China
| | - Bin Jiang
- College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, People’s Republic of China
| | - Wei Jiang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, People’s Republic of China
- College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, People’s Republic of China
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Han X, Ranganathan P, Tzimas C, Weaver KL, Jin K, Astudillo L, Zhou W, Zhu X, Li B, Robbins DJ, Capobianco AJ. Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex. Mol Cancer Res 2017; 15:1173-1183. [PMID: 28584023 DOI: 10.1158/1541-7786.mcr-17-0241] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 05/23/2017] [Accepted: 05/24/2017] [Indexed: 11/16/2022]
Abstract
It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml, and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb Repressor Complex 2 (PRC2) and Lysine Demethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape and repression of transcription. The demethylase activity of LSD1 is a prerequisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex was identified containing LSD1, PRC2, and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis.Implications: This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response. Mol Cancer Res; 15(9); 1173-83. ©2017 AACR.
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Affiliation(s)
- Xiaoqing Han
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.,The Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida
| | - Prathibha Ranganathan
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.,Centre for Human Genetics, Electronic City, Bengaluru, Karnataka, India
| | - Christos Tzimas
- Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Kelly L Weaver
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Ke Jin
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.,The Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida
| | - Luisana Astudillo
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Wen Zhou
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Xiaoxia Zhu
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Bin Li
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - David J Robbins
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Anthony J Capobianco
- Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
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Kim CK, He P, Bialkowska AB, Yang VW. SP and KLF Transcription Factors in Digestive Physiology and Diseases. Gastroenterology 2017; 152:1845-1875. [PMID: 28366734 PMCID: PMC5815166 DOI: 10.1053/j.gastro.2017.03.035] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 03/21/2017] [Accepted: 03/24/2017] [Indexed: 12/14/2022]
Abstract
Specificity proteins (SPs) and Krüppel-like factors (KLFs) belong to the family of transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions. Studies have shown that SPs and KLFs regulate not only physiological processes such as growth, development, differentiation, proliferation, and embryogenesis, but pathogenesis of many diseases, including cancer and inflammatory disorders. Consistently, these proteins have been shown to regulate normal functions and pathobiology in the digestive system. We review recent findings on the tissue- and organ-specific functions of SPs and KLFs in the digestive system including the oral cavity, esophagus, stomach, small and large intestines, pancreas, and liver. We provide a list of agents under development to target these proteins.
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Affiliation(s)
- Chang-Kyung Kim
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY
| | - Ping He
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY
| | - Agnieszka B. Bialkowska
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY,Corresponding Authors: Vincent W. Yang & Agnieszka B. Bialkowska, Department of Medicine, Stony Brook University School of Medicine, HSC T-16, Rm. 020; Stony Brook, NY, USA. Tel: (631) 444-2066; Fax: (631) 444-3144; ;
| | - Vincent W. Yang
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY,Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY,Corresponding Authors: Vincent W. Yang & Agnieszka B. Bialkowska, Department of Medicine, Stony Brook University School of Medicine, HSC T-16, Rm. 020; Stony Brook, NY, USA. Tel: (631) 444-2066; Fax: (631) 444-3144; ;
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Jurkin J, Krump C, Köffel R, Fieber C, Schuster C, Brunner PM, Borek I, Eisenwort G, Lim C, Mages J, Lang R, Bauer W, Mechtcheriakova D, Meshcheryakova A, Elbe-Bürger A, Stingl G, Strobl H. Human skin dendritic cell fate is differentially regulated by the monocyte identity factor Kruppel-like factor 4 during steady state and inflammation. J Allergy Clin Immunol 2017; 139:1873-1884.e10. [PMID: 27742396 PMCID: PMC5538449 DOI: 10.1016/j.jaci.2016.09.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 08/25/2016] [Accepted: 09/09/2016] [Indexed: 11/01/2022]
Abstract
BACKGROUND Langerhans cell (LC) networks play key roles in immunity and tolerance at body surfaces. LCs are established prenatally and can be replenished from blood monocytes. Unlike skin-resident dermal DCs (dDCs)/interstitial-type DCs and inflammatory dendritic epidermal cells appearing in dermatitis/eczema lesions, LCs lack key monocyte-affiliated markers. Inversely, LCs express various epithelial genes critical for their long-term peripheral tissue residency. OBJECTIVE Dendritic cells (DCs) are functionally involved in inflammatory diseases; however, the mechanisms remained poorly understood. METHODS In vitro differentiation models of human DCs, gene profiling, gene transduction, and immunohistology were used to identify molecules involved in DC subset specification. RESULTS Here we identified the monocyte/macrophage lineage identity transcription factor Kruppel-like factor 4 (KLF4) to be inhibited during LC differentiation from human blood monocytes. Conversely, KLF4 is maintained or induced during dermal DC and monocyte-derived dendritic cell/inflammatory dendritic epidermal cell differentiation. We showed that in monocytic cells KLF4 has to be repressed to allow their differentiation into LCs. Moreover, respective KLF4 levels in DC subsets positively correlate with proinflammatory characteristics. We identified epithelial Notch signaling to repress KLF4 in monocytes undergoing LC commitment. Loss of KLF4 in monocytes transcriptionally derepresses Runt-related transcription factor 3 in response to TGF-β1, thereby allowing LC differentiation marked by a low cytokine expression profile. CONCLUSION Monocyte differentiation into LCs depends on activation of Notch signaling and the concomitant loss of KLF4.
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Affiliation(s)
- Jennifer Jurkin
- Institute of Immunology, Medical University of Vienna, Vienna, Austria
| | - Corinna Krump
- Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria
| | - René Köffel
- Institute of Immunology, Medical University of Vienna, Vienna, Austria
| | - Christina Fieber
- Institute of Immunology, Medical University of Vienna, Vienna, Austria
| | - Christopher Schuster
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Patrick M Brunner
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Izabela Borek
- Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria
| | - Gregor Eisenwort
- Institute of Immunology, Medical University of Vienna, Vienna, Austria
| | - Clarice Lim
- Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria; Institute of Immunology, Medical University of Vienna, Vienna, Austria
| | - Jörg Mages
- Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Roland Lang
- Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Wolfgang Bauer
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Diana Mechtcheriakova
- Departments of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | - Anastasia Meshcheryakova
- Departments of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | - Adelheid Elbe-Bürger
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Georg Stingl
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Herbert Strobl
- Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria; Institute of Immunology, Medical University of Vienna, Vienna, Austria.
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Xue YK, Tan J, Dou DW, Chen D, Chen LJ, Ren HP, Chen LB, Xiong XG, Zheng H. Effect of Kruppel-like factor 4 on Notch pathway in hepatic stellate cells. ACTA ACUST UNITED AC 2016; 36:811-816. [PMID: 27924515 DOI: 10.1007/s11596-016-1667-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 10/15/2016] [Indexed: 02/06/2023]
Abstract
The relationship between Kruppel-like factor 4 (KLF4) and the Notch pathway was determined to investigate the effect of KLF4 on the activation of hepatic stellate cells and underlying mechanisms. Fifty SPF BALB/c mice were randomly divided into two groups. A liver fibrosis model was established in 25 mice as the experimental group, and the remaining 25 mice served as controls. On the day 0, 7, 14, and 35, liver tissues were removed for immunofluorescent detection. The Notch pathway inhibitor DAPT was added to the primary original hepatic stellate cells, and KLF4 and Notch-associated factor expression was detected by qRT-PCR. Additionally, the hepatic stellate cell line LX-2 was used to establish control and experimental groups, and was cultured in vitro. LX-2 cells in the experimental groups were treated with DAPT and the Notch activator transforming growth factor-beta 1 separately, whereas those in the control group were given isotonic culture medium. After 48 h, KLF4 expression was examined by Western blotting. After transient transfection of LX-2 cells to increase KLF4, the expression of Notch factor was examined. Immunofluorescence analysis showed that, with the aggravation of liver fibrosis, the absorbance (A) values of KLF4 were decreased (day 0: 980.73±153.19; day 7: 1087.99±230.23; day 14: 390.95±93.56; day 35: 245.99±87.34). The expression of Notch pathway- related factors (Notch-1, Notch-2, and Jagged-1) in the hepatic stellate cell membrane was negatively correlated to KLF4 expression. With the increase of KLF4 expression, Notch-2 (0.73±0.13) and Jagged-1 (0.43±0.12) expression decreased, whereas Notch-1 level was not detectable. When the Notch pathway was inhibited, KLF4 levels generally increased (18.12±1.31). Our results indicate that KLF4 expression is negatively correlated to the Notch pathway in hepatic stellate cells, which may provide a reference for the treatment of hepatic fibrosis.
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Affiliation(s)
- Yin-Kai Xue
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong Univerfsity of Science and Technology, Wuhan, 430022, China
| | - Jun Tan
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong Univerfsity of Science and Technology, Wuhan, 430022, China
| | - Dong-Wei Dou
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong Univerfsity of Science and Technology, Wuhan, 430022, China
| | - Ding Chen
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong Univerfsity of Science and Technology, Wuhan, 430022, China
| | - Lu-Jia Chen
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong Univerfsity of Science and Technology, Wuhan, 430022, China
| | - Huan-Ping Ren
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong Univerfsity of Science and Technology, Wuhan, 430022, China
| | - Li-Bo Chen
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong Univerfsity of Science and Technology, Wuhan, 430022, China
| | - Xin-Gao Xiong
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong Univerfsity of Science and Technology, Wuhan, 430022, China.
| | - Hai Zheng
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong Univerfsity of Science and Technology, Wuhan, 430022, China.
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Wang X, Li X, Huang C, Li L, Qu H, Yu X, Ni H, Cui Q. Kruppel-like factor 4 (KLF-4) inhibits the epithelial-to-mesenchymal transition and proliferation of human endometrial carcinoma cells. Gynecol Endocrinol 2016; 32:772-776. [PMID: 27098518 DOI: 10.3109/09513590.2016.1163673] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Kruppel-like factors (KLFs) are a group of transcriptional regulators, being tumor-suppressive in various types of cancers, but not clear in human endometrial carcinoma (EC). We investigated the KLF-4 expression in both mRNA and protein levels in 29 EC specimens with RT-qPCR and Western blotting methods, and then to determine its promotion to Epithelial-to-mesenchymal transition (EMT) and proliferation of EC Ishikawa cells, via analyzing EMT-associated markers and via CCK-8 and colony forming assay. We found the downregulation of KLF-4 in the 29 EC specimens, correlating with the EC malignance. Moreover, we confirmed reduced levels of EMT and cell proliferation of Ishikawa cells post-KLF-4 overexpression. In conclusion, the significantly reduced KLF-4 correlated with the EC malignance. And the overexpressed KLF-4 promoted the EMT and proliferation of EC cells in vitro. The present study recognized the tumor suppressive role of KLF-4 in EC.
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Affiliation(s)
- Xiaoli Wang
- a Department of Obstetrics and Gynecology , Yantai Yuhuangding Hospital of Qingdao University , Yantai , Shandong , China
| | - Xiaoyan Li
- a Department of Obstetrics and Gynecology , Yantai Yuhuangding Hospital of Qingdao University , Yantai , Shandong , China
| | - Cuiping Huang
- a Department of Obstetrics and Gynecology , Yantai Yuhuangding Hospital of Qingdao University , Yantai , Shandong , China
| | - Lei Li
- a Department of Obstetrics and Gynecology , Yantai Yuhuangding Hospital of Qingdao University , Yantai , Shandong , China
| | - Hongmei Qu
- a Department of Obstetrics and Gynecology , Yantai Yuhuangding Hospital of Qingdao University , Yantai , Shandong , China
| | - Xiaoyan Yu
- a Department of Obstetrics and Gynecology , Yantai Yuhuangding Hospital of Qingdao University , Yantai , Shandong , China
| | - Huijie Ni
- a Department of Obstetrics and Gynecology , Yantai Yuhuangding Hospital of Qingdao University , Yantai , Shandong , China
| | - Qing Cui
- a Department of Obstetrics and Gynecology , Yantai Yuhuangding Hospital of Qingdao University , Yantai , Shandong , China
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Demitrack ES, Samuelson LC. Notch regulation of gastrointestinal stem cells. J Physiol 2016; 594:4791-803. [PMID: 26848053 DOI: 10.1113/jp271667] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 01/19/2016] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal (GI) tract epithelium is continuously replenished by actively cycling stem and progenitor cells. These cell compartments are regulated to balance proliferation and stem cell renewal with differentiation into the various mature cell types to maintain tissue homeostasis. In this topical review we focus on the role of the Notch signalling pathway to regulate GI stem cell function in adult small intestine and stomach. We first present the current view of stem and progenitor cell populations in these tissues and then summarize the studies that have established the Notch pathway as a key regulator of gastric and intestinal stem cell function. Notch signalling has been shown to be a niche factor required for maintenance of GI stem cells in both tissues. In addition, Notch has been described to regulate epithelial cell differentiation. Recent studies have revealed key similarities and differences in how Notch regulates stem cell function in the stomach compared to intestine. We summarize the literature regarding Notch regulation of GI stem cell proliferation and differentiation, highlighting tissue-specific functions to compare and contrast Notch in the stomach and intestine.
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Affiliation(s)
- Elise S Demitrack
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Linda C Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.,Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
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Krüppel-Like Factor 4 (KLF4) Is Not Required for Retinal Cell Differentiation. eNeuro 2016; 3:eN-NWR-0117-15. [PMID: 27022622 PMCID: PMC4770008 DOI: 10.1523/eneuro.0117-15.2016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 11/23/2015] [Accepted: 01/05/2016] [Indexed: 11/22/2022] Open
Abstract
During early vertebrate eye development, a regulatory network of transcription factors regulates retinal cell differentiation and survival into adulthood. Among those factors, Krüppel-like factor 4 (KLF4) plays the dual role of maintaining the stem cell status of retinal progenitors cells and repressing the intrinsic axon regeneration ability in retinal ganglion cells (RGCs) after injury. This study further investigated whether KLF4 plays a role in early retinal cell differentiation or survival into adulthood. We examined different types of retinal neurons, including RGCs, amacrine cells, bipolar cells, Müller cells, and photoreceptor cells, in adult mice in which KLF4 was conditionally deleted in early retinal development using Chx10-promoted Cre by immunohistochemistry. We compared the numbers of retinal neurons and the thickness of photoreceptor and nerve fiber layers between Chx10–Cre-driven KLF4 deletion mice and wild-type mice. There was no significant difference in cell number among any of the retinal cell types or in photoreceptor layer thickness with KLF4 deletion during early development. The thickness of axon bundles in the nerve fiber layer in the Chx10 conditional KLF4 knock-out mice was greater than that in wild-type mice. These results suggest that KLF4 is not required for retinal cell differentiation or survival, but does normally limit retinal ganglion cell axon bundle thickness. These data support a hypothesis that KLF4 suppresses axon growth during development.
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41
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Park CS, Shen Y, Lewis A, Lacorazza HD. Role of the reprogramming factor KLF4 in blood formation. J Leukoc Biol 2016; 99:673-85. [DOI: 10.1189/jlb.1ru1215-539r] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 01/22/2016] [Indexed: 12/31/2022] Open
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Ding B, Liu P, Liu W, Sun P, Wang CL. Emerging roles of Krüppel-like factor 4 in cancer and cancer stem cells. Asian Pac J Cancer Prev 2016; 16:3629-33. [PMID: 25987013 DOI: 10.7314/apjcp.2015.16.9.3629] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Cancer stem cells (CSCs) are rare subpopulations within tumors which are recognized as culprits in cancer recurrence, drug resistance and metastasis. However, the molecular mechanisms of how CSCs are regulated remain elusive. Kruppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with diverse functions in cell differentiation, proliferation, embryogenesis and pluripotency. Recent progress has highlighted the significance of KLFs, especially KLF4, in cancer and CSCs. Therefore, for better therapeutics of cancer disease, it is crucial to develop a deeper understanding of the mechanisms of how KLF4 regulate CSC functions. Herein we summarized the current understanding of the transcriptional regulation of KLF4 in CSCs, and discussed the functional implications of targeting CSCs for potential cancer therapeutics.
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Affiliation(s)
- Bo Ding
- Department of Orthodontics, School of Stomatology, Shandong University, China E-mail :
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43
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Murphy TL, Grajales-Reyes GE, Wu X, Tussiwand R, Briseño CG, Iwata A, Kretzer NM, Durai V, Murphy KM. Transcriptional Control of Dendritic Cell Development. Annu Rev Immunol 2015; 34:93-119. [PMID: 26735697 DOI: 10.1146/annurev-immunol-032713-120204] [Citation(s) in RCA: 323] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The dendritic cells (DCs) of the immune system function in innate and adaptive responses by directing activity of various effector cells rather than serving as effectors themselves. DCs and closely related myeloid lineages share expression of many surface receptors, presenting a challenge in distinguishing their unique in vivo functions. Recent work has taken advantage of unique transcriptional programs to identify and manipulate murine DCs in vivo. This work has assigned several nonredundant in vivo functions to distinct DC lineages, consisting of plasmacytoid DCs and several subsets of classical DCs that promote different immune effector modules in response to pathogens. In parallel, a correspondence between human and murine DC subsets has emerged, underlying structural similarities for the DC lineages between these species. Recent work has begun to unravel the transcriptional circuitry that controls the development and diversification of DCs from common progenitors in the bone marrow.
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Affiliation(s)
- Theresa L Murphy
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Missouri 63110;
| | - Gary E Grajales-Reyes
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Missouri 63110;
| | - Xiaodi Wu
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Missouri 63110;
| | - Roxane Tussiwand
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Carlos G Briseño
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Missouri 63110;
| | - Arifumi Iwata
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Missouri 63110;
| | - Nicole M Kretzer
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Missouri 63110;
| | - Vivek Durai
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Missouri 63110;
| | - Kenneth M Murphy
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Missouri 63110; .,Howard Hughes Medical Institute, Washington University School of Medicine in St. Louis, Missouri 63110
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Vega ME, Giroux V, Natsuizaka M, Liu M, Klein-Szanto AJ, Stairs DB, Nakagawa H, Wang KK, Wang TC, Lynch JP, Rustgi AK. Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett's-like metaplasia via KLF4. Cell Cycle 2015; 13:3857-66. [PMID: 25558829 DOI: 10.4161/15384101.2014.972875] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Barrett's esophagus (BE) is defined as an incomplete intestinal metaplasia characterized generally by the presence of columnar and goblet cells in the formerly stratified squamous epithelium of the esophagus. BE is known as a precursor for esophageal adenocarcinoma. Currently, the cell of origin for human BE has yet to be clearly identified. Therefore, we investigated the role of Notch signaling in the initiation of BE metaplasia. Affymetrix gene expression microarray revealed that BE samples express decreased levels of Notch receptors (NOTCH2 and NOTCH3) and one of the the ligands (JAG1). Furthermore, BE tissue microarray showed decreased expression of NOTCH1 and its downstream target HES1. Therefore, Notch signaling was inhibited in human esophageal epithelial cells by expression of dominant-negative-Mastermind-like (dnMAML), in concert with MYC and CDX1 overexpression. Cell transdifferentiation was then assessed by 3D organotypic culture and evaluation of BE-lineage specific gene expression. Notch inhibition promoted transdifferentiation of esophageal epithelial cells toward columnar-like cells as demonstrated by increased expression of columnar keratins (K8, K18, K19, K20) and glandular mucins (MUC2, MUC3B, MUC5B, MUC17) and decreased expression of squamous keratins (K5, K13, K14). In 3D culture, elongated cells were observed in the basal layer of the epithelium with Notch inhibition. Furthermore, we observed increased expression of KLF4, a potential driver of the changes observed by Notch inhibition. Interestingly, knockdown of KLF4 reversed the effects of Notch inhibition on BE-like metaplasia. Overall, Notch signaling inhibition promotes transdifferentiation of esophageal cells toward BE-like metaplasia in part via upregulation of KLF4. These results support a novel mechanism through which esophageal epithelial transdifferentiation promotes the evolution of BE.
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Affiliation(s)
- Maria E Vega
- a Division of Gastroenterology; Department of Medicine ; University of Pennsylvania ; Philadelphia , PA , USA
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Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses. Immunity 2015; 42:916-28. [PMID: 25992862 DOI: 10.1016/j.immuni.2015.04.017] [Citation(s) in RCA: 302] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 02/15/2015] [Accepted: 04/29/2015] [Indexed: 01/14/2023]
Abstract
The two major lineages of classical dendritic cells (cDCs) express and require either IRF8 or IRF4 transcription factors for their development and function. IRF8-dependent cDCs promote anti-viral and T-helper 1 (Th1) cell responses, whereas IRF4-expressing cDCs have been implicated in controlling both Th2 and Th17 cell responses. Here, we have provided evidence that Kruppel-like factor 4 (Klf4) is required in IRF4-expressing cDCs to promote Th2, but not Th17, cell responses in vivo. Conditional Klf4 deletion within cDCs impaired Th2 cell responses during Schistosoma mansoni infection, Schistosoma egg antigen (SEA) immunization, and house dust mite (HDM) challenge without affecting cytotoxic T lymphocyte (CTL), Th1 cell, or Th17 cell responses to herpes simplex virus, Toxoplasma gondii, and Citrobacter rodentium infections. Further, Klf4 deletion reduced IRF4 expression in pre-cDCs and resulted in selective loss of IRF4-expressing cDCs subsets in several tissues. These results indicate that Klf4 guides a transcriptional program promoting IRF4-expressing cDCs heterogeneity.
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McCauley HA, Guasch G. Three cheers for the goblet cell: maintaining homeostasis in mucosal epithelia. Trends Mol Med 2015; 21:492-503. [PMID: 26144290 DOI: 10.1016/j.molmed.2015.06.003] [Citation(s) in RCA: 158] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 05/28/2015] [Accepted: 06/09/2015] [Indexed: 12/16/2022]
Abstract
Many organs throughout the body maintain epithelial homeostasis by employing a mucosal barrier which acts as a lubricant and helps to preserve a near-sterile epithelium. Goblet cells are largely responsible for secreting components of this mucosal barrier and represent a major cellular component of the innate defense system. In this review we summarize what is known about the signaling pathways that control goblet cell differentiation in the intestine, the lung, and the ocular surface, and we discuss a novel functional role for goblet cells in mucosal epithelial immunology. We highlight the cell type-specificity of the circuitry regulating goblet cell differentiation and shed light on how changes to these pathways lead to altered goblet cell function, a prominent feature of mucosa-associated diseases.
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Affiliation(s)
- Heather A McCauley
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnett Avenue, Cincinnati, OH 45229, USA
| | - Géraldine Guasch
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnett Avenue, Cincinnati, OH 45229, USA; CRCM, Inserm UMR1068, Département d'Oncologie Moléculaire, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Univ, UM 105, 13009, Marseille, France.
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Kaur K, Saxena A, Larsen B, Truman S, Biyani N, Fletcher E, Baliga MS, Ponemone V, Hegde S, Chanda A, Fayad R. Mucus mediated protection against acute colitis in adiponectin deficient mice. JOURNAL OF INFLAMMATION-LONDON 2015; 12:35. [PMID: 25949213 PMCID: PMC4422601 DOI: 10.1186/s12950-015-0079-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 04/15/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Acute ulcerative colitis is an inflammation-driven condition of the bowel. It hampers the general homeostasis of gut, resulting in decreased mucus production and epithelial cell renewal. Adiponectin (APN), an adipocytokine, is secreted by the adipose tissue and has been debated both as a pro-inflammatory or anti-inflammatory protein depending on the disease condition and microenvironment. The present study delineates the role of APN depletion in mucus modulation in a model of acute colitis. METHODS APNKO and C57BL/6 (WT) male mice were given 2% DSS ad libidum for 5 days in drinking water, followed by normal drinking water for the next 5 days. Hematoxyline-eosin and Alcian Blue staining was used to observe the general colonic morphology and goblet cell quantification respectively. Protein expression levels were quantified by Western blot for MATH1, Hes1, MUC2 and MUC4. ELISA was used to study the levels of TNF-α, IL-6 and IL-1β. RESULTS APNKO mice showed significantly higher goblet to epithelial cell ratios, lower pro-inflammatory cytokines and higher MUC2 levels as compared to the WT mice. The protein expression levels for the mucin MUC2 supported the histopathological findings. An increase in colon tissue-secreted levels of pro-inflammatory with a reduction in anti-inflammatory cytokines in presence of APN support the pro-inflammatory role of APN during acute inflammation. CONCLUSION Absence of APN is protective against DSS-induced acute colonic inflammation by means of reducing colon tissue-secreted pro-inflammatory cytokines, modulating goblet and epithelial cell expressions, and increasing the levels of secretory mucin MUC2.
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Affiliation(s)
- Kamaljeet Kaur
- Department of Exercise Science, University of South Carolina, Columbia, SC 29208 USA.,Arnold School of Public Health, Applied Physiology Division, University of South Carolina, 921 Assembly St. room 303B, Columbia, SC 29208 USA
| | - Arpit Saxena
- Department of Exercise Science, University of South Carolina, Columbia, SC 29208 USA
| | - Bianca Larsen
- Department of Exercise Science, University of South Carolina, Columbia, SC 29208 USA
| | - Samantha Truman
- Department of Exercise Science, University of South Carolina, Columbia, SC 29208 USA
| | - Nathan Biyani
- Department of Exercise Science, University of South Carolina, Columbia, SC 29208 USA
| | - Emma Fletcher
- Department of Exercise Science, University of South Carolina, Columbia, SC 29208 USA
| | | | | | - Shweta Hegde
- Department of Exercise Science, University of South Carolina, Columbia, SC 29208 USA
| | - Anindya Chanda
- Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208 USA.,Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208 USA
| | - Raja Fayad
- Department of Exercise Science, University of South Carolina, Columbia, SC 29208 USA.,Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208 USA
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Táncos Z, Bock I, Nemes C, Kobolák J, Dinnyés A. Cloning and characterization of rabbit POU5F1, SOX2, KLF4, C-MYC and NANOG pluripotency-associated genes. Gene 2015; 566:148-57. [PMID: 25895477 DOI: 10.1016/j.gene.2015.04.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 03/16/2015] [Accepted: 04/12/2015] [Indexed: 12/19/2022]
Abstract
While the rabbit (Oryctolagus cuniculus) is an important research model for aspects of human development and disease that cannot be studied in rodents, the lack of data on the genetic regulation of rabbit preimplantation development is a limitation. To assist in the understanding of this process, our aim was to isolate and characterize genes necessary for the induction and maintenance of cellular pluripotency. We are the first to report the isolation of complete coding regions of rabbit SOX2, KLF4, C-MYC and NANOG, which encode transcription factors that play crucial regulatory roles during early mammalian embryonic development. We determined the exon-intron boundaries and chromosomal localization of these genes using computational analysis. The sequences of mRNA and translated protein of the newly identified genes and those of POU5F1 were aligned to their mammalian orthologs to determine the degree of evolutionary conservation. Furthermore, the expression of these genes in embryonic and adult cells was studied at the mRNA and protein levels. We found the sequences and the expression pattern of these pluripotency-associated genes to be highly conserved between human and rabbit, indicating that the rabbit would be a valuable model for human preimplantation development. Implementing the newly identified genes either as biomarkers or as reprogramming factors might also pave the way towards the creation of stable pluripotent rabbit cell lines.
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Affiliation(s)
- Zsuzsanna Táncos
- Molecular Animal Biotechnology Laboratory, Szent István University, Gödöllő, Hungary; Biotalentum Ltd, Gödöllő, Hungary
| | - István Bock
- Molecular Animal Biotechnology Laboratory, Szent István University, Gödöllő, Hungary; Biotalentum Ltd, Gödöllő, Hungary
| | | | | | - András Dinnyés
- Molecular Animal Biotechnology Laboratory, Szent István University, Gödöllő, Hungary; Biotalentum Ltd, Gödöllő, Hungary; Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
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Simmen RCM, Heard ME, Simmen AM, Montales MTM, Marji M, Scanlon S, Pabona JMP. The Krüppel-like factors in female reproductive system pathologies. J Mol Endocrinol 2015; 54:R89-R101. [PMID: 25654975 PMCID: PMC4369192 DOI: 10.1530/jme-14-0310] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling, leading to aberrant cell proliferation, survival, and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets, and involve a range of paracrine and autocrine regulatory circuits. The members of the Krüppel-like factor (KLF) family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Herein, we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms, and discuss their potential as targets for therapeutic intervention.
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Affiliation(s)
- Rosalia C M Simmen
- Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USADepartment of Obstetrics and GynecologyUniversity of Michigan Health System, Ann Arbor, Michigan 48109, USADepartment of Internal MedicineHarlem Hospital Center, Columbia University Medical Center, New York, New York 10037, USA
| | - Melissa E Heard
- Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USADepartment of Obstetrics and GynecologyUniversity of Michigan Health System, Ann Arbor, Michigan 48109, USADepartment of Internal MedicineHarlem Hospital Center, Columbia University Medical Center, New York, New York 10037, USA
| | - Angela M Simmen
- Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USADepartment of Obstetrics and GynecologyUniversity of Michigan Health System, Ann Arbor, Michigan 48109, USADepartment of Internal MedicineHarlem Hospital Center, Columbia University Medical Center, New York, New York 10037, USA
| | - Maria Theresa M Montales
- Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USADepartment of Obstetrics and GynecologyUniversity of Michigan Health System, Ann Arbor, Michigan 48109, USADepartment of Internal MedicineHarlem Hospital Center, Columbia University Medical Center, New York, New York 10037, USA
| | - Meera Marji
- Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USADepartment of Obstetrics and GynecologyUniversity of Michigan Health System, Ann Arbor, Michigan 48109, USADepartment of Internal MedicineHarlem Hospital Center, Columbia University Medical Center, New York, New York 10037, USA
| | - Samantha Scanlon
- Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USADepartment of Obstetrics and GynecologyUniversity of Michigan Health System, Ann Arbor, Michigan 48109, USADepartment of Internal MedicineHarlem Hospital Center, Columbia University Medical Center, New York, New York 10037, USA
| | - John Mark P Pabona
- Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USADepartment of Obstetrics and GynecologyUniversity of Michigan Health System, Ann Arbor, Michigan 48109, USADepartment of Internal MedicineHarlem Hospital Center, Columbia University Medical Center, New York, New York 10037, USA
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Suman S, Das TP, Ankem MK, Damodaran C. Targeting Notch Signaling in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2014; 10:411-416. [PMID: 25395896 DOI: 10.1007/s11888-014-0252-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The activation of Notch signaling is implicated in tumorigenesis in the colon due to the induction of pro-survival signaling in colonic epithelial cells. Chemoresistance is a major obstacle for treatment and for the complete eradication of colorectal cancer (CRC), hence, the inhibition of Notch is an attractive target for CRC and several groups are working to identify small molecules or monoclonal antibodies that inhibit Notch or its downstream events; however, toxicity profiles in normal cells and organs often impede the clinical translation of these molecules. Dietary agents have gained momentum for targeting several pro-survival signaling cascades, and recent studies demonstrated that agents that inhibit Notch signaling result in growth inhibition in preclinical models of CRC. In this review, we focus on the importance of Notch as a preventive and therapeutic target for colon cancer and on the effect of WA on this signaling pathway in the context of colon cancer.
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Affiliation(s)
- Suman Suman
- Department of Urology, University of Louisville, Louisville, KY 40202
| | - Trinath P Das
- Department of Urology, University of Louisville, Louisville, KY 40202
| | - Murali K Ankem
- Department of Urology, University of Louisville, Louisville, KY 40202
| | - Chendil Damodaran
- Department of Urology, University of Louisville, Louisville, KY 40202
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